Entirely noninvasive neuromodulation achieved using low-intensity focused ultrasound (US) is one of the most exciting frontiers in neuroscience today. US is emerging as a new way of stimulating specific regions of the brain noninvasively through the skull of animals and humans. In comparison to other noninvasive alternatives such as transcranial magnetic stimulation (TMS) or transcranial electrical stimulation (tDCS, tACS), US propagates deep into the brain while also retaining a sharp spatial focus. TMS is currently used to treat neuropathic pain and major depressive disorder. US will provide a much more focused alternative, with fewer side effects, to treat these disorders. The method may also be used as a noninvasive and focused alternative to deep brain stimulation (DBS). However, it is unknown how US stimulates neurons and what stimulus parameters researchers and clinicians should use to achieve optimal stimulation. The principal investigator (PI) has a background in neural engineering, including pharmacological neuromodulation and electrophysiology. To elucidate the mechanism of US neuromodulation and to work toward optimal stimulation, the PI will pursue training through the K99 Pathway to Independence Award mechanism at Stanford University. He has three faculty members with expertise in diverse aspects of US neuromodulation as mentors. In the mentored phase, the PI and colleagues will identify which neurons and ion channels are activated by US using a small invertebrate (C. elegans) as a model. Using this animal, the PI will also rapidly establish the set of optimal stimulation parameters. In a translational part of the training, the PI, within an interdisciplinary team at Stanford, will build on these findings to determine optimal stimulus parameters in a large mammal (sheep). To do so, they will ultrasonically stimulate a deep brain structure, verify the US focus using MR imaging, and record EEG responses. This work will also establish safety threshold at which there is no detectable tissue damage. The training will teach the PI five skills essential to attain independence. He will learn how to i) conduct mechanistic investigations at the circuit level ii) perform US stimulation in large animals iii) mentor a student to conduct US experiments iv) establish collaborations and v) present findings. In the independent phase, the PI and his students will apply this training. They will build on the optimal stimulus and safety data to devise optimal stimulation protocols in species with which the PI worked previously: macaque monkeys and humans. The monkey will serve to optimize the effectiveness and validate the safety of the approach before it will be advanced to humans. Together, this research will elucidate how US activates neurons, and provide a set of US parameters that activates neurons efficiently. It is expected that this knowledge will provide a new tool to study the function of neural circuits and open doors for clinical applications to alleviate neurological disorders.